RESUMO
Nonselective glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists are efficacious in chronic pain but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in the central nervous system (CNS). Recently, LY3130481 has been shown to selectively block AMPA receptors coassembled with the auxiliary protein, transmembrane AMPA receptor regulatory protein (TARP) γ8, which is highly expressed in the hippocampus but also in pain pathways, including anterior cingulate (ACC) and somatosensory cortices and the spinal cord, suggesting that selective blockade of γ8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant γ8-containing AMPA receptors was modulated by coexpression with other TARPs; γ2 subunits affected activity more than γ3 subunits. Consistent with these findings, LY3130481 had decreasing potency on receptors from rat hippocampal, cortical, spinal cord, and cerebellar neurons that was replicated in tissue from human brain. LY3130481 partially suppressed, whereas the nonselective AMPA antagonist GYKI53784 completely blocked, AMPA receptor-dependent excitatory postsynaptic potentials in ACC and spinal neurons in vitro. Similarly, LY3130481 attenuated short-term synaptic plasticity in spinal sensory neurons in vivo in response to stimulation of peripheral afferents. LY3130481 also significantly reduced nocifensive behaviors after intraplantar formalin that was correlated with occupancy of CNS γ8-containing AMPA receptors. In addition, LY3130481 dose-dependently attenuated established gait impairment after joint damage and tactile allodynia after spinal nerve ligation, all in the absence of motor side effects. Collectively, these data demonstrate that LY3130481 can suppress excitatory synaptic transmission and plasticity in pain pathways containing γ8/AMPA receptors and significantly reduce nocifensive behaviors, suggesting a novel, effective, and safer therapy for chronic pain conditions.
Assuntos
Canais de Cálcio/metabolismo , Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Terapia de Alvo Molecular , Receptores de AMPA/metabolismo , Animais , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Dor Crônica/fisiopatologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Distribuição TecidualRESUMO
We identified a di-substituted triazolopyrimidine with anti-tubercular activity against Mycobacterium tuberculosis. Three segments of the scaffold were examined rationally to establish a structure-activity relationship with the goal of improving potency and maintaining good physicochemical properties. A number of compounds displayed sub-micromolar activity against Mycobacterium tuberculosis with no cytotoxicity against eukaryotic cells. Non-substituted aromatic rings at C5 and a two-carbon chain connecting a terminal aromatic at C7 were preferred features; the presence of NH at C7 and a lack of substituent at C2 were essential for potency. We identified compounds with acceptable metabolic stability in rodent and human liver microsomes. Our findings suggest that the easily-synthesized triazolopyrimidines are a promising class of potent anti-tubercular agents and warrant further investigation in our search for new drugs to fight tuberculosis.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Triazóis/química , Animais , Antituberculosos/química , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.
Assuntos
Antidepressivos/química , Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Ácido Glutâmico/análogos & derivados , Ácido Glutâmico/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Antidepressivos/farmacocinética , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacocinética , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Transtorno Depressivo Maior/metabolismo , Cães , Ácido Glutâmico/farmacocinética , Haplorrinos , Hexanos/química , Hexanos/farmacocinética , Hexanos/farmacologia , Humanos , Células Madin Darby de Rim Canino , Camundongos , Ratos , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.
Assuntos
Isoquinolinas/farmacologia , Dor/tratamento farmacológico , Pró-Fármacos/farmacologia , Receptores de Ácido Caínico/antagonistas & inibidores , Tetrazóis/farmacologia , Administração Oral , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Isoquinolinas/química , Masculino , Dados de Sequência Molecular , Pró-Fármacos/química , Ratos , Ratos Sprague-Dawley , Receptores de Ácido Caínico/química , Relação Estrutura-Atividade , Tetrazóis/químicaRESUMO
The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.
Assuntos
Isoquinolinas/farmacologia , Dor/tratamento farmacológico , Pró-Fármacos/farmacologia , Receptores de Ácido Caínico/antagonistas & inibidores , Administração Oral , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Haplorrinos , Isoquinolinas/química , Dados de Sequência Molecular , Pró-Fármacos/química , Receptores de Ácido Caínico/química , Relação Estrutura-AtividadeRESUMO
The American Chemical Society Division of Medicinal Chemistry (MEDI) confers a range of awards, fellowships and honors to recognize excellence in medicinal chemistry. To celebrate the creation of the Gertrude Elion Medical Chemistry Award the ACS MEDI Division wishes to take this opportunity to inform the community of the many awards, fellowships and travel grants that are available for members.
RESUMO
AMPA receptors mediate fast excitatory transmission in the brain. Neuronal AMPA receptors comprise GluA pore-forming principal subunits and can associate with multiple modulatory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and CNIHs (cornichons). AMPA receptor potentiators and non-competitive antagonists represent potential targets for a variety of neuropsychiatric disorders. Previous studies showed that the AMPA receptor antagonist GYKI-53655 displaces binding of a potentiator from brain receptors but not from recombinant GluA subunits. Here, we asked whether AMPA receptor modulatory subunits might resolve this discrepancy. We find that the cerebellar TARP, stargazin (γ-2), enhances the binding affinity of the AMPA receptor potentiator [(3)H]-LY450295 and confers sensitivity to displacement by non-competitive antagonists. In cerebellar membranes from stargazer mice, [(3)H]-LY450295 binding is reduced and relatively resistant to displacement by non-competitive antagonists. Coexpression of AMPA receptors with CNIH-2, which is expressed in the hippocampus and at low levels in the cerebellar Purkinje neurons, confers partial sensitivity of [(3)H]-LY450295 potentiator binding to displacement by non-competitive antagonists. Autoradiography of [(3)H]-LY450295 binding to stargazer and γ-8-deficient mouse brain sections, demonstrates that TARPs regulate the pharmacology of allosteric AMPA potentiators and antagonists in the cerebellum and hippocampus, respectively. These studies demonstrate that accessory proteins define AMPA receptor pharmacology by functionally linking allosteric AMPA receptor potentiator and antagonist sites.
Assuntos
Benzodiazepinas/farmacologia , Membrana Celular/metabolismo , Proteínas do Ovo/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Proteínas de Membrana/metabolismo , Células de Purkinje/metabolismo , Receptores de AMPA , Regulação Alostérica/genética , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Membrana Celular/genética , Proteínas do Ovo/genética , Células HEK293 , Humanos , Proteínas de Membrana/genética , Camundongos , Receptores de AMPA/agonistas , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/genética , Receptores de AMPA/metabolismoRESUMO
The identification and development of new anti-tubercular agents are a priority research area. We identified the trifluoromethyl pyrimidinone series of compounds in a whole-cell screen against Mycobacterium tuberculosis. Fifteen primary hits had minimum inhibitory concentrations (MICs) with good potency IC90 is the concentration at which M. tuberculosis growth is inhibited by 90% (IC90 < 5 µM). We conducted a structure-activity relationship investigation for this series. We designed and synthesized an additional 44 molecules and tested all analogs for activity against M. tuberculosis and cytotoxicity against the HepG2 cell line. Substitution at the 5-position of the pyrimidinone with a wide range of groups, including branched and straight chain alkyl and benzyl groups, resulted in active molecules. Trifluoromethyl was the preferred group at the 6-position, but phenyl and benzyl groups were tolerated. The 2-pyridyl group was required for activity; substitution on the 5-position of the pyridyl ring was tolerated but not on the 6-position. Active molecules from the series demonstrated low selectivity, with cytotoxicity against eukaryotic cells being an issue. However, there were active and non-cytotoxic molecules; the most promising molecule had an MIC (IC90) of 4.9 µM with no cytotoxicity (IC50 > 100 µM). The series was inactive against Gram-negative bacteria but showed good activity against Gram-positive bacteria and yeast. A representative molecule from this series showed rapid concentration-dependent bactericidal activity against replicating M. tuberculosis bacilli with ~4 log kill in <7 days. Overall the biological properties were promising, if cytotoxicity could be reduced. There is scope for further medicinal chemistry optimization to improve the properties without major change in structural features.
RESUMO
Compared with NMDA receptor-dependent LTP, much less is known about the mechanism of induction of NMDA receptor-independent LTP; the most extensively studied form of which is mossy fiber LTP in the hippocampus. In the present study we show that Ca2+-induced Ca2+ release from intracellular stores is involved in the induction of mossy fiber LTP. This release also contributes to the kainate receptor-dependent component of the pronounced synaptic facilitation that occurs during high-frequency stimulation. We also present evidence that the trigger for this Ca2+ release is Ca2+ permeation through kainate receptors. However, these novel synaptic mechanisms can be bypassed when the Ca2+ concentration is raised (from 2 to 4 mM), via a compensatory involvement of L-type Ca2+ channels. These findings suggest that presynaptic kainate receptors at mossy fiber synapses can initiate a cascade involving Ca2+ release from intracellular stores that is important in both short-term and long-term plasticity.
Assuntos
Cálcio/metabolismo , Potenciação de Longa Duração/fisiologia , Fibras Musgosas Hipocampais/fisiologia , Receptores de Ácido Caínico/metabolismo , Transmissão Sináptica/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Animais Recém-Nascidos , Venenos de Artrópodes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Interações Medicamentosas , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Espaço Extracelular , Técnicas In Vitro , Isoquinolinas/farmacologia , Ácido Caínico/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Magnésio/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Fibras Musgosas Hipocampais/efeitos dos fármacos , Nifedipino/farmacologia , Técnicas de Patch-Clamp , Ratos , Receptores de Ácido Caínico/antagonistas & inibidores , Receptores de Ácido Caínico/efeitos dos fármacos , Rianodina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Tapsigargina/farmacologiaRESUMO
Developments in the molecular biology and pharmacology of GLU(K5), a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLU(K5)-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLU(K5)-containing kainate receptors prevented development of epileptiform activity--evoked by the muscarinic agonist, pilocarpine--and inhibited the activity when it was pre-established. In conscious rats, these GLU(K5) antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLU(K5) antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLU(K5) kainate receptor antagonists offer a potential new therapy for epilepsy.
Assuntos
Epilepsia/prevenção & controle , Antagonistas de Aminoácidos Excitatórios/farmacologia , Sistema Límbico/efeitos dos fármacos , Pilocarpina , Receptores de Ácido Caínico/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Animais , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Estimulação Elétrica , Eletrochoque , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Humanos , Técnicas In Vitro , Isoquinolinas/farmacologia , Ácido Caínico/farmacologia , Sistema Límbico/fisiopatologia , Masculino , Camundongos , Ratos , Ratos Wistar , Especificidade por Substrato , Resultado do TratamentoRESUMO
The hypothesis that kainate receptor blockade would be associated with anxiolytic-like effects was tested with a selective ligand, 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884). LY382884 selectively binds the GLU(K5) kainate receptor subunit (K(b)=0.6 microM) and has 30 microM or greater affinity for cloned human AMPA receptor subtypes. The anxiolytic potential of LY382884 was tested in rats responding under a Vogel conflict procedure, a pharmacologically validated model for the prediction of antianxiety efficacy in humans. Both the benzodiazepine anxiolytic chlordiazepoxide and LY382884 increased suppressed licking without affecting rates of non-suppressed licking. In contrast, an AMPA receptor selective antagonist, 7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-7-carboxamide, 5-(4-aminophenyl)-8,9-dihydro-N,8-dimethyl-, monohydrochloride (9CI) (GYKI53655), did not increase suppressed responding. The finding that a selective GLU(K5) receptor antagonist produced anxiolytic-like effects in an animal model predictive of efficacy in humans combined with data in the literature on glutamatergic modulation of anxiety suggests that kainate receptor sensitivity to glutamate might be an important mediating event in the pathophysiological expression of anxiety states. The selective targeting of kainate receptors with an antagonist could therefore be a novel pharmacological mechanism to treat anxiety disorders.
Assuntos
Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Isoquinolinas/farmacologia , Receptores de Ácido Caínico/fisiologia , Animais , Benzodiazepinas/farmacologia , Ligação Competitiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Transformada , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Plasma/efeitos dos fármacos , Plasma/metabolismo , Subunidades Proteicas , Ratos , Ratos Sprague-DawleyRESUMO
Metabotropic glutamate 2/3 (mGlu2/3) receptors are of considerable interest owing to their role in modulating glutamate transmission via presynaptic, postsynaptic and glial mechanisms. As part of our ongoing efforts to identify novel ligands for these receptors, we have discovered (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; (LY3020371), a potent and selective orthosteric mGlu2/3 receptor antagonist. In this account, we characterize the effects of LY3020371 in membranes and cells expressing human recombinant mGlu receptor subtypes as well as in native rodent and human brain tissue preparations, providing important translational information for this molecule. In membranes from cells expressing recombinant human mGlu2 and mGlu3 receptor subtypes, LY3020371.HCl competitively displaced binding of the mGlu2/3 agonist ligand [3H]-459477 with high affinity (hmGlu2 Ki = 5.26 nM; hmGlu3 Ki = 2.50 nM). In cells expressing hmGlu2 receptors, LY3020371.HCl potently blocked mGlu2/3 agonist (DCG-IV)-inhibited, forskolin-stimulated cAMP formation (IC50 = 16.2 nM), an effect that was similarly observed in hmGlu3-expressing cells (IC50 = 6.21 nM). Evaluation of LY3020371 in cells expressing the other human mGlu receptor subtypes revealed high mGlu2/3 receptor selectivity. In rat native tissue assays, LY3020371 demonstrated effective displacement of [3H]-459477 from frontal cortical membranes (Ki = 33 nM), and functional antagonist activity in cortical synaptosomes measuring both the reversal of agonist-suppressed second messenger production (IC50 = 29 nM) and agonist-inhibited, K+-evoked glutamate release (IC50 = 86 nM). Antagonism was fully recapitulated in both primary cultured cortical neurons where LY3020371 blocked agonist-suppressed spontaneous Ca2+ oscillations (IC50 = 34 nM) and in an intact hippocampal slice preparation (IC50 = 46 nM). Functional antagonist activity was similarly demonstrated in synaptosomes prepared from epileptic human cortical or hippocampal tissues, suggesting a translation of the mGlu2/3 antagonist pharmacology from rat to human. Intravenous dosing of LY3020371 in rats led to cerebrospinal fluid drug levels that are expected to effectively block mGlu2/3 receptors in vivo. Taken together, these results establish LY3020371 as an important new pharmacological tool for studying mGlu2/3 receptors in vitro and in vivo. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.
Assuntos
Cicloexanos/farmacocinética , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Linhagem Celular , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cicloexanos/química , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/química , Humanos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.
Assuntos
Anticonvulsivantes/farmacologia , Benzotiazóis/farmacologia , Cerebelo/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Prosencéfalo/efeitos dos fármacos , Pirazóis/farmacologia , Piridonas/farmacologia , Receptores de AMPA/antagonistas & inibidores , Animais , Anticonvulsivantes/efeitos adversos , Canais de Cálcio/metabolismo , Cerebelo/metabolismo , Convulsivantes/toxicidade , Modelos Animais de Doenças , Tontura/induzido quimicamente , Epilepsia/induzido quimicamente , Camundongos , Nitrilas , Pentilenotetrazol/toxicidade , Prosencéfalo/metabolismo , Piridonas/efeitos adversos , Ratos , Receptores de AMPA/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológicoRESUMO
Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (-)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (-)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients.
Assuntos
Canais de Cálcio/metabolismo , Descoberta de Drogas , Receptores de AMPA/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores de AMPA/metabolismoRESUMO
As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. The resulting cocrystal structure revealed the specific ligand-protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu2 IC50 value.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Descoberta de Drogas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Antidepressivos/síntese química , Antidepressivos/química , Encéfalo/efeitos dos fármacos , Cicloexanos/síntese química , Cicloexanos/química , Cicloexanos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/isolamento & purificação , Relação Estrutura-Atividade , NataçãoRESUMO
Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.
Assuntos
Aminoácidos/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Dor/tratamento farmacológico , Receptores de Ácido Caínico/antagonistas & inibidores , Analgésicos/farmacocinética , Animais , Disponibilidade Biológica , Linhagem Celular , Modelos Animais de Doenças , Humanos , Hiperalgesia/tratamento farmacológico , Ratos , Receptores de AMPA/metabolismo , Proteínas Recombinantes/metabolismo , Medula Espinal/fisiopatologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismoRESUMO
RATIONALE: In vitro studies have identified a series of decahydroisoquinoline compounds with differential selectivity for the subunits that comprise AMPA/kainic acid receptors. Compounds have been identified that have preferential activity at AMPA receptors (LY302679), whereas others (LY377770) have affinity for GluR5-kainic acid preferring subunit, which is activated by ATPA and kainic acid. OBJECTIVES: These studies set out to determine if locomotor activity could differentiate these profiles in vivo. METHODS: Locomotor activity was assessed in photocell drums in male Lister Hooded rats. RESULTS: AMPA, kainic acid and the GluR5 selective agonist ATPA, all suppressed spontaneous locomotor activity (SLA) in rats at doses of 1.0, 5.0 and 20 mg/kg resp. All three agonists achieve micromolar concentrations measured in whole brain after dosing with 10 mg/kg SC. The decahydroisoquinoline antagonist compounds, LY302679 (GluR2), LY293558 (GluR2, 5) and LY377770 (GluR5) all decreased SLA in rats (ED(min) 2.5, 5.0 and 20 mg/kg respectively). The rank order of potency at GluR2 subunits (LY302679>LY293558>LY377770) was reflected in the same rank order of activity for suppression of SLA. LY293558 reversed the suppression of SLA induced by all three agonists (0.62--2.5 mg/kg). LY377770 reversed the effects of ATPA only (ED(min) 1.0 mg/kg), LY302679 (ED(min) 2.5 mg/kg) attenuated the effect of kainic acid but was ineffective against AMPA and ATPA. CONCLUSIONS: Both agonist and antagonist suppression of SLA is associated with greater affinity for the GluR2 subunit, while compounds with affinity for the GluR5 subunit were less potent in suppressing SLA.
Assuntos
Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Isoquinolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de AMPA/efeitos dos fármacos , Receptores de Ácido Caínico/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Isoxazóis/farmacologia , Ácido Caínico/farmacologia , Masculino , Propionatos/farmacologia , Ratos , Receptores de AMPA/agonistas , Receptores de AMPA/antagonistas & inibidores , Receptores de Ácido Caínico/agonistas , Receptores de Ácido Caínico/antagonistas & inibidores , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologiaRESUMO
The authors review the history of controversy regarding conflict versus deficit. They suggest that conflict, when conceptualized within the theory of self psychology, may arise in one of two ways, either: (1) along with deficit when caregivers are unable to provide developmentally needed selfobject functions, and, at the same time, these needed caregivers are also feared; these conflicts are unconscious and potentially pathogenic. Or: (2) conflicts may appear secondary to deficit. Such conflicts also require the analysis of selfobject transferences that have arisen on the basis of the underlying deficit. A clinical example demonstrates that deficit related to the oedipal phase may give rise to oedipal-selfobject transferences, requiring their working through for a successful termination.
Assuntos
Conflito Psicológico , Ego , Terapia Psicanalítica , Adulto , Humanos , Masculino , Apego ao Objeto , Teoria PsicanalíticaRESUMO
The group II metabotropic glutamate receptor (mGluR) antagonists LY341495 and LY366457 were profiled for their effects on locomotor activity in mice. Both compounds significantly increased locomotor activity. Observational studies showed that rearing was also selectively increased. LY366457-induced hyperactivity was significantly attenuated by the selective D1 dopamine receptor antagonist SCH23390 and also by the D2 dopamine receptor antagonist haloperidol but only at doses that significantly suppressed spontaneous locomotion. The selective 5-HT(2A) antagonist MDL100907 had no effect on LY366457-induced hyperactivity, while the less selective 5-HT(2A-C) antagonist ritanserin had only a modest effect. In all cases, the doses of antagonists that reduced the locomotor response to LY366457 were greater than those previously shown to reduce the locomotor response to the psychostimulants amphetamine and cocaine and MK-801. Pretreatment with reserpine also significantly attenuated the response to LY366457, possibly implicating a monoaminergic substrate in the mediation of this effect. The phenomenonology and pharmacology of the locomotor activation induced by the mGluR antagonists differs markedly from that induced by locomotor stimulants such as amphetamine, cocaine or MK-801. These results suggest that group II mGluRs may be involved in the tonic suppression of locomotor and exploratory activity, and this suppression can be disinhibited in the presence of a group II mGluR antagonist.
Assuntos
Aminoácidos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Xantenos/farmacologia , Animais , Benzazepinas/farmacologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Fluorbenzenos/farmacologia , Haloperidol/farmacologia , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Hipercinese/veterinária , Camundongos , Piperidinas/farmacologia , Antagonistas da Serotonina/farmacologia , Fatores de TempoRESUMO
The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-d-Tic-d-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K(i) = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K(i) = 6600 nM). Sulfonamide 39 (K(i) = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K(i) = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K(i) = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.